Endothelial-to-Mesenchymal Transition in Chronic Kidney Disease: Mechanisms and Therapeutic Targets

Renal fibrosis is the final common pathological outcome of chronic kidney disease (CKD) and a major driver of progression to end-stage kidney disease. Endothelial-to-mesenchymal transition (EndMT) is a phenotypic process in which endothelial cells lose their endothelial identity and acquire mesenchymal or myofibroblast-like characteristics, contributing to extracellular matrix accumulation, capillary rarefaction, microvascular dysfunction, and fibrotic remodeling. Transforming growth factor-β (TGF-β) is a central inducer of EndMT through both canonical Smad-dependent and non-canonical Smad-independent signaling pathways. Other pathways, including Wnt/β-catenin, Notch, Hedgehog, inflammatory cytokine signaling, autophagy dysregulation, oxidative stress, and metabolic reprogramming, further modulate EndMT in the diseased kidney. Despite growing evidence implicating EndMT in renal fibrosis, the quantitative contribution of EndMT to human CKD progression and the most effective therapeutic strategies to target this process remain incompletely defined. This review summarizes the cellular and molecular mechanisms of EndMT relevant to CKD, highlights key regulatory pathways and pathway crosstalk, and discusses emerging pharmacological approaches to limit EndMT, preserve microvascular integrity, and attenuate renal fibrogenesis.